This invention relates to a series of phthalimido arylpiperazine derivatives, pharmaceutical compositions containing them as well as processes and intermediates used in their manufacture. The compounds of the invention selectively inhibit binding to the xcex11a adrenergic receptor, a receptor which has been implicated in benign prostatic hyperplasia. As such the compounds are potentially useful in the treatment of this disease.
Benign prostatic hyperplasia (BPH), a nonmalignant enlargement of the prostate, is the most common benign tumor in men. Approximately 50% of all men older than 65 years have some degree of BPH and a third of these men have clinical symptoms consistent with bladder outlet obstruction (Hieble and Caine, 1986). In the U.S., benign and malignant diseases of the prostate are responsible for more surgery than diseases of any other organ in men over the age of fifty.
There are two components of BPH, a static and a dynamic component. The static component is due to enlargement of the prostate gland, which may result in compression of the urethra and obstruction to the flow of urine from the bladder. The dynamic component is due to increased smooth muscle tone of the bladder neck and the prostate itself (which interferes with emptying of the bladder) and is regulated by alpha 1 adrenergic receptors (xcex11-ARs). The medical treatments available for BPH address these components to varying degrees, and the therapeutic choices are expanding.
Surgical treatment options address the static component of BPH and include transurethral resection of the prostate (TURP), transurethral incision of the prostate (TUIP), open prostatectomy, balloon dilatation, hyperthermia, stents and laser ablation. TURP is the preferred treatment for patients with BPH and approximately 320,000 TURPs were performed in the U.S. in 1990 at an estimated cost of $2.2 billion (Weis et al., 1993). Although an effective treatment for most men with symptomatic BPH, approximately 20-25% of patients do not have a satisfactory long-term outcome (Lepor and Rigaud, 1990). Complications include retrograde ejaculation (70-75% of patients), impotence (5-10%), postoperative urinary tract infection (5-10%), and some degree of urinary incontinence (24%) (Mebust et al., 1989). Furthermore, the rate of reoperation is approximately 15-20% in men evaluated for 10 years or longer (Wennberg et al., 1987).
Apart from surgical approaches, there are some drug therapies which address the static component of this condition. Finasteride (Proscarxe2x80x9d, Merck), is one such therapy which is indicated for the treatment of symptomatic BPH. This drug is a competitive inhibitor of the enzyme 5xcex1-reductase which is responsible for the conversion of testosterone to dihydrotestosterone in the prostate gland (Gormley et a)., 1992). Dihydrotestosterone appears to be the major mitogen for prostate growth, and agents which inhibit 5xcex1-reductase reduce the size of the prostate and improve urine flow through the prostatic urethra. Although finasteride is a potent 5xcex1-reductase inhibitor and causes a marked decrease in serum and tissue concentrations of dihydrotestosterone, it is only moderately effective in treating symptomatic BPH (Oesterling, 1995). The effects of finasteride take 6-12 months to become evident and for many men the clinical improvement is minimal (Barry, 1997).
The dynamic component of BPH has been addressed by the use of adrenergic receptor blocking agents (xcex11-AR blockers) which act by decreasing the smooth muscle tone within the prostate gland itself. A variety of xcex11-AR blockers (terazosin, prazosin, and doxazosin) have been investigated for the treatment of symptomatic bladder outlet obstruction due to BPH, with terazosin (Hytrinxe2x80x9d, Abbott) being the most extensively studied. Although the xcex11-AR blockers are well-tolerated, approximately 10-15% of patients develop a clinically adverse event (Lepor, 1995). The undesirable effects of all members of this class are similar, with postural hypotension being the most commonly experienced side effect (Lepor et al., 1992). In comparison to the 5xcex1-reductase inhibitors, the xcex11-AR blocking agents have a more rapid onset of action (Steers, 1995). However, their therapeutic effect, as measured by improvement in the symptom score and the peak urinary flow rate, is moderate. (Oesterling, 1995)
The use of xcex11-AR antagonists in the treatment of BPH is related to their ability to decrease the tone of prostatic smooth muscle, leading to relief of the obstructive symptoms. Adrenergic receptors are found throughout the body play a dominant role in the control of blood pressure, nasal congestion, prostrate function and other processes (Harrison et al., 1991). However, there are a number of cloned xcex11-AR receptor subtypes: xcex11a-AR, xcex11b-AR and xcex11d-AR (Bruno et al., 1991; Forray et al., 1994; Hirasawa et al., 1993; Ramarao et al., 1992; Schwinn et al., 1995; Weinberg et al., 1994). A number of labs have characterized the xcex11-ARs in human prostate by functional, radioligand binding, and molecular biological techniques (Forray et al., 1994; Hatano et al., 1994; Marshall et al., 1992; Marshall et al., 1995; Yamada et al., 1994). These studies provide evidence in support of the concept that the xcex11a-AR subtype comprises the majority of xcex11-ARs in human prostatic smooth muscle and mediates contraction in this tissue. These findings suggest that the development of a subtype-selective xcex11a-AR antagonist might result in a therapeutically effective agent with reduced side effects for the treatment of BPH.
The compounds of this invention selectively bind to the xcex11a-AR receptor, antagonize the activity of said receptor and are selective for prostate tissue over aortic tissue. As such, these represent a viable treatment for BHP without the side effects associated with known xcex11-AR antagonists.
The invention includes compounds of Formula I 
wherein:
R1 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R2 is C1-6alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenyC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
R3 is hydrogen, hydroxy or C1-5alkoxy if the hashed line is absent or is oxygen if the hashed line is present;
R4 is hydrogen, C1-5alkyl, phenylC1-5alkyl or substituted phenylC1-5alkyl
where the phenyl substitutents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl;
R5 is hydrogen, halogen, hydroxy, C1-8alkyl, substituted C1-8alkyl
where the alkyl substitutents are independently selected from one or more halogens,
xe2x80x83C1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, C1-5alkylcarbonyl, C1-5alkoxycarbonyl, nitrile, or nitro;
R6 is hydrogen, halogen, hydroxy, C1-8alkyl, substituted C1-8alkyl
where the alkyl substitutents are independently selected from one or more halogens,
xe2x80x83C1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, C1-5alkylcarbonyl, C1-5alkoxycarbonyl, or nitro;
R7 is hydrogen, halogen, hydroxy, C1-8alkyl, substituted C1-8alkyl
where the alkyl substitutents are independently selected from one or more halogens,
xe2x80x83C1-5alkoxy, amino, C1-5alkylamino, diC1-5alkylamino, C1-5alkylcarbonyl, C1-5alkoxycarbonyl, or nitro;
A is nitrogen or carbon;
B is nitrogen or carbon;
E is nitrogen or carbon;
with the proviso that only one of A, B, or E is nitrogen;
pharmaceutically acceptable salts thereof; and
stereoisomers, racemic mixtures, as well as enantiomers thereof.
In addition this invention contemplates pharmaceutical compositions containing an effective dose of compounds of Formula I. Still further this invention contemplates methods of treating diseases associated with the xcex11a adrenergic receptor consisting of administering an effective dose of a compound of Formula I to a mammal. This invention also contemplates a method of treating benign prostatic hyperplasia consisting of administering an effective dose of a compound of Formula I to a mammal.
Aside from compounds of Formula I, this invention contemplates intermediate compounds of Formula II and Formula III. These intermediates are useful in the preparation of compounds of Formula I and are as follows: 
wherein
R8 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R9 is C1-6alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenylC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
R10 is hydrogen, C1-5alkoxycarbonyl, phenylC1-5alkoxycarbonyl or allyloxycarbonyl;
R11 is hydrogen, phenylC1-5alkyl, or substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and nitro; 
xe2x80x83wherein
R10 is C1-5alkoxycarbonyl, phenylC1-5alkoxycarbonyl, or allyloxycarbonyl;
R11 is phenylC1-5alkyl, or substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and nitro;
R12 is halogen, mesyl, tosyl, or hydroxy.
Still further the invention contemplates methods of making compounds of Formula II. Those methods are as follows: Reacting a compound of Formula III 
wherein
R10 is C1-5alkoxycarbonyl, phenylC1-5alkoxycarbonyl, or allyloxycarbonyl;
R11 is phenylC1-5alkyl, or substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and nitro;
R12 is halogen, mesyl, tosyl, or hydroxy.
with a piperazine derivative of Formula IV 
wherein
R8 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R9 is C1-5alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenylC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
in the presence of a basic reagent to produce a compound for Formula II 
wherein
R8 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R9 is C1-6alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenylC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
R10 is C1-5alkoxycarbonyl, phenylC1-5alkoxycarbonyl, or allyloxycarbonyl;
R11 is phenylC1-5alkyl, or substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and nitro;
Reacting a compound of Formula II 
wherein
R8 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R9 is C1-6alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenylC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
R10 is C1-5alkoxycarbonyl, phenylC1-5alkoxycarbonyl, or allyloxycarbonyl;
R11 is phenylC1-5alkyl, or substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and nitro;
with an acidic reagent to give a compound of Formula II 
wherein
R8 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R9 is C1-6alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenylC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
R10 is hydrogen
R11 is phenylC1-5alkyl, or substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and nitro;
Reacting a compound of Formula II 
wherein
R8 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R9 is C1-6alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenylC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
R10 is hydrogen
R11 is phenylC1-5alkyl, or substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and nitro;
with a reducing agent to give a compound of Formula II 
wherein
R8 is hydrogen, halogen, C1-5alkoxy, hydroxyl, or C1-5alkyl;
R9 is C1-6alkyl, substituted C1-6alkyl
where the alkyl substituents are independently selected from one or more halogens,
xe2x80x83phenyl,
xe2x80x83substituted phenyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, C1-5alkoxy, and trihaloC1-5alkyl,
xe2x80x83phenylC1-5alkyl, or
xe2x80x83substituted phenylC1-5alkyl
where the phenyl substituents are independently selected from one or more members of the group consisting of C1-5alkyl, halogen, C1-5alkoxy, and trihaloC1-5alkyl;
R10 is hydrogen;
R11 is hydrogen;